The presence of Michael acceptors as contaminants in pharmaceutical agents, food or other compositions that might be internalized by living organisms is generally undesirable, since Michael acceptors can undergo cytotoxic reactions with nucleophilic cellular constituents. Of particular concern are potentially genotoxic reactions of Michael acceptors with nucleic acid nucleophiles (e.g. Chem. Res. Toxicol. 2004, 17, 827-838; Chem. Res. Toxicol. 1991, 4, 50-7; Environmental Health Perspectives 1990, 88, 99-106).
Interestingly, animals have defense systems for deactivating internalized or metabolically generated Michael acceptors. One such deactivating system involves reaction of Michael acceptors with the endogenous cellular nucleophile, reduced glutathione, to form glutathione adducts (for a review see Advances in Enzyme Regulation 1993, 33, 281-296). Recent studies (Bioorg. Med. Chem. 1999, 7, 2849-2855; Chem. Commun. 2005, 886-888) indicate that this reaction is reversible. Thus, the genotoxic and carcinogenic potential of Michael acceptors may reflect a failure of the Michael acceptor to undergo complete reaction with glutathione or reversal of thiol addition. Consequently, it is important to minimize the amount of Michael acceptor contaminants (or Michael acceptor precursors) that are present in drugs and other products meant for administration to living organisms.
A recently published patent application (20050222188A1) entitled, “Process for preparing oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone” describes a method for removal of the Michael acceptor 14-hydroxycodeinone from the analgesic composition oxycodone that involves hydrogenating in acidic solution an oxycodone hydrochloride composition that contains contaminating 14-hydroxycodeinone.
Whereas techniques like those described in 20050222188A1 (and elsewhere) exist for removal and detection of Michael acceptor contaminants, improvements would increase the safety of drugs and other compositions consumed by living organisms.